Acyl amevo-nitrothiazole compositions



United States Patent ACYL AMINO-NITROTHIAZOLE COMPOSITIONS FOR ORAL ADMINISTRATION IN CONTROL OF TRICHOMONAS VAGINALIS VAGINITIS Alfred B. Kupferberg, Somerville, William C. Mende, Neshanic, Nathan Millman, Somerville, and Heron O. Singher, Plainfield, N. J., assignors to Ortho Pharmaceutical Corporation, a corporation of New Jersey No Drawing. Application October 21, 1952,

7 Serial No. 316,088

12 Claims. (Cl. 167-55) The present invention relates to a new and improved therapeutic tablet for the treatment of certain protozoan infections, and more particularly to a novel and highly effective pharmaceutical preparation designed for the treatment of Trichomonas vaginalis vaginitis.

Trichomonas vaginalis, a parasitic protozoon primarily infests the human vagina and is the ethological agent of a very troublesome and prevalent form of vaginal infestation known as Trichomonas vaginalis vaginitis.

Various medicaments and methods of treatment have heretofore been employed in the treatment of T richomonas vaginalis vaginitis, particularly by topical application to the vaginal mucosa, but all have been subjected to numerous limitations and disadvantages. Organic acids such as acetic, lactic, and citric acids are commonly used topically but are characterized by very low trichomonadicidal action, and in many instances they fail satisfactorily to clear up the infestation, even when the therapy is continued for long periods of time. Silver picrate, another agent in common topical use, has good trichomonadicidal properties but is objectionable for it frequently gives rise to severe sensitization's, argyria and the like, and also because it produces aesthetically inacceptable stains. Phenyl mercuric nitrate or acetate are active trichomonadicidal compounds, but are reported to be unstable except at a limited pH range (7.4 to 7.6) which diiiers considerably from the pH of a human vagina moderately or heavily infested with Trichomonas vaginalzr. Other preparations comprising various agents in powdered form such as boric acid, diiodoquinone, lactose, dextrose, and silver picrate, are commonly applied to an infested vagina by insufiiation. However, vaginal insufilation of pregnant women has been reported to result in air embolisms and death, and this method is now seriously criticized and infrequently used. For these and other reasons, a more satisfactory trichomonadicide has long been desired and in particular a trichomonadicide effective by oral administration has been desired.

The object of the present invention is to provide a new and improved therapeutic tablet for the treatment of Trichomonas vaginalis vaginitis, with a view to obviating the disadvantages of the medicaments and modes of treatment heretofore employed.

A more particular object is the provision of a therapeutic tablet characterized by high, trichomonadicidal power and capable of giving symptomatic relief to patients suffering from Trichomonas vaginalis vaginitis.

Still another object is the provision of a tablet which is free of adverse side reactions upon the patient and is characterized by a high degree of efiicacy in the treatment of Trichomonas vaginalis vaginitis.

Other objectsand advantages of the invention will become apparent as the description progresses.

The foregoing objectives may be attained in. accordance with the present invention which .is based on the discovery that therapeutic formulations in the form of tablets or capsules, or ent ris coated tablets or capsules 2,735,798 Patented Feb 21, 1956 "ice containing an acyl derivative of 2-amino-5-nitrothiazole as the active agent and an inert solid diluent have tri-.

chomonadicidal activity of a high order and upon oral administration result in prompt relief from the symptoms of Trichomonas vaginalis vaginitis and a high incidence of cures. Acyl derivatives of Z-amino-S-nitrothiazole are represented by the general formula in which R is an acyl radical. Acyl derivatives of Z-amino- 5-nitr0thiaz0le in which the acyl radical is acetyl, propinyl, butyrl, isobutyrl, caproyl, or lauroyl have been found particularly effective trichomonadicidal agents for use in the formulations of this invention.

The in vitro trichomonadicidal activity of acyl derivatives of Z-aminO-S-nitrothiazole has been established by a series of tests which established the minimal inhibitory concentration of these compounds. Minimal inhibitory concentration, as used above, is defined as the minimalconcentrationof a trichomonadicidal compound capable of preventing the growth of and killing Trichomonas vaginalis organisms introduced into a culture medium, capable alone of supporting a vigorous growth of the organisms, and containing the trichomonadicidal compound to be tested. The culture medium used in the tests is described in a publication of Kupferberg, Johnson and Sprince, Proceedings of the Society for Experimental Biology and Medicine, volume 67, pages 304-308, 1948.

in making the tests to determine minimal inhibitory concentrations, 0.05 ml. of a 48-hour culture of Trichomonus vaginalis was placed in a series of tubes containing 10 ml. of the culture medium and increasing amounts of' the compound to be tested. The inoculated culture medium was then incubated at 37 C. for nine days and ex- Minimal Inhibitory Concentration, gamma per cc.

Compound 2-amino-5-nitrothiazo1e 13.

2-aeetylamino-5-nitrothiazole.; 0 33-1. 20 2-propionylamino.-. 2. 30 2-butyr oylamino- 0 47-0. 94 2-eaproylamino 0. 93 2'iso-caproylamino 1; 2-lauroylamiuo 1. 10

In employing the trichomonadicides in the present invention for the treatment of T rich'omomzs vaginalis vaginitis, one or more of the active agents are uniformly dis tributed in a suitable vehicle that is chemically compatible with the particular trichomonadicide selected, formed into a tablet and in a specific embodiment of the invention, the tablet is coated or surrounded with an en'teric coating in the nature of a layer or film of material which is substantially soluble in or disintegrated and removed by intestinal secretions but substantially insoluble in gastric juices and secretions or disintegrated and removed thereby.

The minimal inhibitory concentration of the Inert diluents or fillersarechosen which arechemically compatible with the trichomonadicidal agent. Satisfactory diluents include lactose, dextrose, sucrose, sodium chloride, glycine, kaolin and starch. Itis desirable. that a binder such as acacia, zein, tragacanth, gelatin, sodium carboxymethylcellulose, or methyl cellulose and also, in order that a tablet maybe readily prepared, that a lubricant such as magnesium stearate, zinc stearate, mineral oil, stearic acid, stearyl alcohol or monoand polyglycol esters also be intimately admixed with the filler and active agent. The above ingredients including the trichomonadicidal material, may beformed into a tablet by thoroughly mixing the ingredients in a moist condition, granulating and compressing the mixture into tablets by conventional methods.

It is preferred that an alkaline material also be present in the'tablet formulation because the solubility of the acyl derivatives of 2-acetylamino-S-nitrothiazole is low at an acid 'pH but issubstantially increased'at an alkaline pH. 2-acetylan1ino-5-nitrothiazole has a solubility in water at pH 5.6 of about one part in 50,000 by weight, Whereas the solubility in water at pH 7.0 by weight is about ten times as great. The presence in the formulation of an alkaline agent assists in solubilizing the active agent. Satisfactory alkaline agents include aluminum hydroxide, disodium phosphate, dipotassium phosphate, sodium carbonate, sodium bicarbonate and alkaline or alkaline earth salts of glycine.

In the preferred modification of the invention, the tablet or capsule is coated or surrounded with a composition which is substantially soluble in or disintegrated by intestinal secretions but substantially insoluble in and not disintegrated'by the secretions of the stomach. The trichomonadicidal agents are more effective when administered in the form of an enteric or coated tablet or capsule and it is believed that this is due to the fact that the active ingredients are many times more soluble in an alkaline than in an acid medium. Because of the alkaline nature of intestinal fluids, the active ingredients are more readily solubilized and absorbed therein. There is also some possibility that the acyl group may be removed from the amino group of the active agents by prolonged contact with gastric juices by hydrolysis, and this would result in the conversion of the 2-acylamino-5-nitrothiazole into 2-amino-5-nitrothiazole which, has been demonstrated to have less in vitro trichomonadicidal activity than its acyl derivatives.

Any conventional enteric coating is suitable for use in coating-or surrounding the tablets or capsules of this invention. Examples of coatings which have been found satisfactory include acid-insoluble, alkali-soluble ion exchange resins, high-melting fats of both animal and vegetable origin, high-melting vegetable Waxes such as carnauba wax and bees wax, lipid materials such as glyceryl esters of fatty acids, esters of polyhydric compounds such as long chain fatty acidpartial esters of hexitol anhydrides and oxyalkylene derivatives of long'chain fatty acid partial esters of hexitol anhydrides; natural resins such as gum mastic, shellac, and rosin; fat-soluble compounds such as abietic a cid, bile acids and cholesterol; as well as cellulose derivatives such as cellulose nitrate, cellulose acetate, cellulose derivatives containing free carboxyl groups such as cellulose phthalate and cellulose acetate-phthalate, non-toxic water-soluble salts of polyvinyl phthalates and phenyl salicylate; or mixtures of any of the above compounds.

The enteric coatings may be formed into a capsule in which the active agents in association with an inert filler 1s contained. In general, a tablet may be coated by dipping directly into a solution of an enteric coating material capable of being put into solution in a suitable solvent. It is also contemplated that a powder or tablet containing the active agent in association with the inert ingredients may first be coated with or engaged in gelatin and then dipped into a solution in a suitable solvent of an enteric coating.materialsuszh.asfin OLUliQnfiL DsY, QQ LQ IQQ: ture of the cellulose derivatives listed above. The thick-- ness of the coating of the tablet or capsule may be controlled by varying the concentration of the solution of the ester in the solvent. A plurality of immersions to form a plurality of coatings may also be used. Certain enteric coating materials, such as cellulose'derivatives, are adapt-- ed to be formed into capsules composed of separate telescoping units into which the medicament may be placed and sealed therein by the application of a small amount of solution of the enteric coating material at the edge of' the telescoping segments. The enteric coating material may be, for example, about'five percent to ten per cent of the weight of thetablet or other form of the medica-- ment.

Acyl derivatives of Z-amino-S-nitrothiazole may be present in the formulations of the above examples in amounts ranging from 200 milligrams to 500 milligrams and be highly effective in the treatment of Trichomonas vaginalis vaginitis; however, it is preferred that about 300 milligrams of the trichomonadicidal agent be present.

In order to disclose more clearly the nature of the: present invention several specific examples will hereafter be described in considerable detail. It should be understood that they are presented solely for purposes of illustration and not with the object of either delineating the scope of the application or restricting the scope of the appended claims. The amounts in the examples are expressed in milligrams.

Example I Z-acetylamino-S-nitrothiazole 300 Dipotassium phosphate 50 Acacia 50 Magnesium stearate Lactose 70 Example I1 2-acetylamino-5-nitrothiazole 300 Dipotassium phosphate 50 Acacia 5O Magnesium stearate 3O Lactose 70 Cellulose acetate-phthalate 50 Example III 2-propionylamino-5-nitrothiazole 350 Disodium phosphate 50 Gum tragacanth 50 Stearic acid Dextrose 75 Example IV 2-propionylamino-5-nitrothiazole 350 Disodium phosphate 50 Gum tragacanth 50 Stearic acid 35 Dextrose 75 Phenylsalicylate Example V 2-caproylamino-S-nitrothiazole 400 Aluminum hydroxide Gelatin Zinc stearate 30 Sucrose Example VI 2-caproylamino-5-nitrothiazole 400 Aluminum hydroxide 45 Gelatin 55 Zinc stearate 30 Sucrose 70 Gum mastic 55 Example VII 2-lauroylamino-5-nitrothiazole 425 Dipotassium phosphate 50 Acacia 50 Stearic acid 35 Dextrose 65 Example VIII It will be apparent to those skilled in the art that numerous variations, modifications, and extensions of the principles involved may be made without departing from the spirit and scope of the invention. Thus, for example, the inert ingredients and enteric coating materials employed in the various examples are merely illustrative and it will be apparent that many others may be used in place of those illustrated in the examples. Likewise, acyl derivatives of Z-amino-S-nitrothiazole other than those specifically mentioned may be used either singly or in combination. All such variations, modifications, and extensions are to be understood as included within the ambit of the appended claims.

What is claimed is:

1. A composition of matter in dosage unit form for oral administration effective in the control of Trichomonas vaginalis vaginitis which comprises a compound of the formula in which R is an acyl radical in intimate admixture with an inert solid diluent and surrounded by an enteric layer of substance which is substantially insoluble in acid stomach secretions and soluble in alkaline intestinal fluids. 2. A composition of matter in dosage unit form for oral administration effective in the control of Trichomonas vaginalis vaginitis which comprises a compound of the formula H-0-N ll lg NOr-C NHR in which R is an acyl radical having not more than ten carbon atoms in intimate admixture with an inert solid diluent and surrounded by an enteric layer of a substance which is substantially insoluble in acid stomach secretions and soluble in alkaline intestinal fluids.

3. A composition according to claim 2 in which R is an acetyl radical.

4. A composition of matter in the form of a tablet for oral administration which is effective in the control of Trichomonas vaginalis vaginitis which comprises a compound of the formula in which R is an acyl radical having not more than ten carbon atoms in intimate admixture with an inert solid diluent, a binder, an alkaline material, and a lubricant.

5. A composition of matter in the form of a tablet for oral administration which is effective in the control of Trichomonas vaginalis vaginitis which comprises a compound of the formula HCN LE ll NOz- C-NHR in which R is an acyl radical having not more than ten carbon atoms in intimate admixture with an inert solid diluent, a binder, an alkaline material, and a lubricant; and surrounded by an enteric layer of a substance which is substantially insoluble in acid stomach secretions and soluble in alkaline intestinal fluids.

6. A composition according to claim 5 in which the enteric layer is composed of cellulose acetatephthalate.

7. A composition according to claim 5 in which the enteric layer is composed of phenyl salicylate.

8. A composition according to claim 5 in which the enteric layer is composed of gum mastic.

9. A composition of matter in the form of a tablet for oral administration which is eflective in the control of T richomonas vaginalis vaginitis comprising Z-acetylamino-S-nitrothiazole intimately admixed with lactose, acacia, magnesium stearate and dipotassium phosphate.

10. A composition of matter in the form of a tablet for oral administration which is effective in the control of Trichomonas vaginalis vaginitis comprising Z-acetylamino-S-nitrothiazole intimately admixed with lactose, acacia, magnesium stearate, and dipotassium phosphate; and surrounded by an enteric layer of a substance which is substantially insoluble in acid stomach secretions and soluble in alkaline intestinal fluids.

11. A composition according to claim 10 in which the enteric layer is composed of cellulose acetate-phthalate.

12. A composition of matter in dosage unit form for oral administration effective in the control of Trichomonas vaginalis vaginitis which comprises the compound of the formula:

HCN Nor-il (PF-NEH.

in which R is an acyl radical, in intimate admixture with an inert solid diluent and sealed in a gelatine capsule.

References Cited in the file of this patent UNITED STATES PATENTS 2,531,756 Waletsky NOV. 28, 1950 

1. A COMPOSITION OF MATTER IN DOSAGE UNIT FORM FOR ORAL ADMINISTRATION EFFECTIVE IN THE CONTROL OF TRICHOMONAS VAGINALIS VAGINITIS WHICH COMPRISES A COMPOUND OF THE FORMULA 